Background Information

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1 What is Velcade (bortezomib)? Velcade (bortezomib) is a medicine used to treat a blood cancer known as multiple myeloma, and was the first of the treatments in the class of anti-cancer drugs known as proteasome inhibitors. 1 Multiple myeloma, also known as myeloma, is a type of cancer that develops from cells in the bone marrow called plasma cells. 2 Myeloma is the second most common type of blood cancer, representing about 15% of all blood cancers in the UK 3 and 1.5% of all cancers (about 3 in every 200). 4 Just under 4,800 people in the UK are diagnosed with myeloma each year. 4 It mainly occurs in people over the age of 60 and affects slightly more men than women. 3 It is twice as common in black populations as it is in white and Asian populations. 4 Overall, about 70 out of every 100 people (70%) diagnosed with myeloma in England, Wales and Scotland live for at least a year after diagnosis. About 37 out of every 100 (37%) live for at least 5 years. It is estimated that between 15 and 19 people in every 100 (15 to 19%) will live for at least 10 years. 5 In non ASCT eligible patients, a long term five-year follow-up analysis published in 2011 reported that treatment with bortezomib, in combination with melphalan and prednisone (VMP) delivered median overall survival of nearly 5 years (56.4 months) for patients randomised to VMP compared to 3.6 years (43.1 months) [HR 0.695, p=0.0004] for patients randomised to MP, reflecting a 13.3 month increase in median overall survival and a 31% reduced risk of death with VMP. 8 How does it work? Bortezomib works by temporarily blocking the actions of proteasomes. Proteasomes are involved in the removal, breakdown and recycling of damaged proteins, or those that are no longer needed by the cell. As a consequence of temporarily blocking the actions of proteasomes, these proteins build up and become toxic, confusing the cell, and so cause it to die. 1 Dividing myeloma cells rely more heavily on proteasomes than normal healthy cells, which divide slowly. They are therefore more sensitive to bortezomib. Although healthy cells are affected by bortezomib, they are able to survive and recover quickly from the dose of bortezomib used to treat myeloma. 1 1

2 How is it administered? Treatment for myeloma is often most effective when two or more drugs, with different but synergistic and complementary mechanisms of action, are given together. Other anti cancer treatments, such as the chemotherapy drug melphalan may also be given as part of the treatment combination. 1 When it is used: * Bortezomib can be used in combination with melphalan and prednisone for patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with a bone marrow transplant 9 * Bortezomib can be used as monotherapy to treat progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation 9 When it was originally introduced, bortezomib was given intravenously (into the vein), however it can now also be given as a subcutaneous (under the skin) injection. 9 Intravenous injection The reconstituted solution is administered as a three to five second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/ml (0.9%) solution for injection. 9 Intravenous injections are administered at the concentration of 1 mg/ml (3.5mg bortezomib reconstituted with 3.5mL normal [0.9%] saline). 9,10 Subcutaneous injection Bortezomib can now be given as a subcutaneous injection. 9 Data from an international, phase 3 study presented in 2011, involving patients with relapsed multiple myeloma, clearly showed that subcutaneous bortezomib was noninferior in terms of efficacy compared with intravenous administration whilst also producing significantly lower rates of peripheral neuropathy, a well known and important side-effect of bortezomib. Significantly lower rates of peripheral neuropathy of all grades of severity were recorded, despite similar rates of potential risk factors in the subcutaneous and intravenous groups. 10 Subcutaneous injections are administered at 2.5 mg/ml (3.5 mg bortezomib reconstituted with 1.4mL normal [0.9%] saline) to limit the volume injected. 9,10 This is a higher concentration of bortezomib to that used intravenously, which means that the same amount of medication is delivered through a smaller volume. 2

3 When used subcutaneously, Velcade must be reconstituted differently to when it is used intravenously (IV). In order to reduce the risk of any potential administration and reconstitution errors please contact the Medical Information Department at Janssen ( cilag.co.uk or tel: ). Treatment with bortezomib The aim of anti-myeloma treatment is to relieve symptoms and prolong life by reducing the number of myeloma cells in the bone marrow thereby also reducing the paraprotein levels in the blood and/or free light chains in the urine. A response to treatment usually corresponds to an improvement in quality of life. 1 Myeloma can respond well to treatment. 11 Both the level (amount the paraprotein decreases) and duration of response (length of plateau or remission) are important when measuring how successful treatment has been. 12 Response to treatment can be referred to as a complete response (CR) or a partial response (PR). Complete response means that the cancer can't be detected on scans, X-rays, or blood tests, etc. 13 In practical terms, it means less than 5% of plasma cells in the bone marrow and no detectable paraprotein. 14 Partial response means that the treatment has killed some of the cells, but not all. 13 In practical terms, it means that there has been a greater or equal to 50% reduction of paraprotein in blood, and a greater or equal to 90% reduction in 24 hour urinary paraprotein. 14 Newly diagnosed myeloma Data from the pivotal clinical study called the VISTA trial suggested that over 70% of newly diagnosed patients, not considered suitable for high-dose therapy and stem cell transplantation, who were treated with a combination of VMP achieved a PR or CR lasting for an average of 19.9 months. 8 An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant overall survival (OS) benefit with VMP. 8 Adverse events reported during treatment included haematological events (thrombocytopenia, neutropenia and anaemia), gastrointestinal events, infections and nervous system disorders including peripheral neuropathy. Other conditions such as pyrexia, fatigue, and anorexia were also noted. 15 3

4 Relapsed myeloma Data from the extended analysis of another pivotal international clinical study (the APEX trial) indicated that over 40% of relapsed myeloma patients had a PR or CR following intravenous treatment with bortezomib alone. In this study the median duration of response to Velcade was 7.8 months. 16 Adverse events reported during bortezomib monotherapy included peripheral neuropathy and thrombocytopenia, various gastrointestinal disorders, fatigue, hypercalcemia, and spinal cord compression. 17 VISTA and APEX are the two registration studies for bortezomib. Please note these were IV studies. Bortezomib has a well characterised side effect profile and a favourable benefit risk ratio in its licensed indications. However, as with all drugs, bortezomib has a number of potential side-effects. They vary considerably from patient to patient and may be mild or more serious. As side effects can usually be treated or managed, it is very important that a patient highlights them promptly to their doctor/nurse. 1 Additional Information Nurse Time By eliminating the need for repeated intravenous access, insertion of a long-term central venous device, and there being no need to dress the injection site, subcutaneous administration could save on staff nurse time. Pricing There is no difference in price between subcutaneous and intravenous formulations of bortezomib. For both, the cost of one vial containing 3.5mg of powder is Potential savings to the NHS could be realised through the averted acquisition costs for cannula, extension filter, saline and gravity giving set, 9 saving approximately 4.54 per patient, 21 per administration. This equates to per patients course of subcutaneously administered bortezomib (based on 32 vials per course). 9,19 For more information on side effects refer to the Summary of Product Characteristics. To access the full Summary of Product Characteristics (SPC), please visit the electronic Medicines compendium (emc), at: References 1 Velcade and Myeloma. Infoguide Series. Available at: 2 About Myeloma A quick guide. Available at: bout-myeloma.pdf. 4

5 3 Myeloma UK What causes Myeloma? Available at: 4 Cancer Research UK Myeloma risks and causes. Available at 5 Cancer Research UK Stats & Outlook for Myeloma. Available at: Last accessed Child, A.J. et al. High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma. N Engl J Med 2003;348: Harousseau, J.L. & Moreau, P. Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med 2009;360: San Miguel, S. F et al. Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan- Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial. Blood (ASH Annual Meeting Abstracts) 2011; 118: Abstract Velcade Summary of Product Characteristics available at: 10 Moreau, P et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncology. 2011;12(5): Cancer Research UK The Stages of Myeloma. Available at: 12 Myeloma UK Myeloma: Essential Guide. Available at: 13 CRUK How Chemotherapy works. Available at: 14 Myeloma UK. Response to treatment. Available at: 15 San Miguel, S. F et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med 2008; 359: Richardson, P. G et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007;110: Richardson et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med 2005; 352: DATA ON FILE: Janssen-Cilag Ltd VELCADE_SC_DOF_Jan2012_OR_MS_002: Subcutaneous bortezomib, administration time and resource use when subcutaneously administering bortezomib as opposed to the original intravenously administered bortezomib Costing Template and report: Bortezomib monotherapy for relapsed multiple myeloma 20 British National Formulary 63; BMJ Group & Pharmaceutical Press, March DATA ON FILE: Janssen-Cilag Ltd. VELCADE_SC_DOF_Jan2012_OR_MS_003: Subcutaneous bortezomib, resource use when using intravenously administered bortezomib